tbuckley/cabot-search huggingface dataset:
A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression
Authors: Jing Ge, Ronghua Tan, Qian Gao, Rui Li, Pengxin Xu, Hang Song, Shenqi Wang, Ying Wan, Lei Zhou
Journal: Advanced Healthcare Materials (2023)

Ketamine (KA), commonly used as an anesthetic, is now widely studied as an antidepressant for the treatment of depression. However, due to its side effects, such as addiction and cognitive impairment, the dosage and frequency of (S)-ketamine approved by the FDA for the treatment of refractory depression is very low, which limits its efficacy. Here, a new multifunctional nanocarrier system (AC-RM@HA-MS) with specific targeting capabilities is developed to improve the efficacy of KA treatment. KA-loaded NPs (AC-RM@HA-MS-KA) are constructed with a multilayer core-shell structure. KA-loaded mesoporous silica NPs are prepared, conjugated with hyaluronic acid (HA) as pore gatekeepers, and sheathed with an RBC-membrane (RM) for camouflage. Finally, the surface is tagged with bifunctional peptides (Ang-2-Con-G, AC) to achieve specific targeting. One peptide (Ang-2) is acted as a guide to facilitate the crossing of the blood-brain barrier (BBB), while the other (Con-G) is functioned as a ligand for the targeted delivery of KA to the N-methyl-D-aspartate receptor sites. Animal experiments reveal that AC-RM@HA-MS-KA NPs effectively cross the BBB and directionally accumulate in the curing areas, thereby alleviating the depressive symptoms and improving the cognitive functions of depressed mice. After treatment, the depressed mice almost completely return to normal without obvious symptoms of addiction.
The tumour ecology of quiescence: Niches across scales of complexity
Authors: Simon P. Castillo, Felipe Galvez-Cancino, Jiali Liu, Steven M. Pollard, Sergio A. Quezada, Yinyin Yuan
Journal: Seminars in Cancer Biology (2023)

Quiescence is a state of cell cycle arrest, allowing cancer cells to evade anti-proliferative cancer therapies. Quiescent cancer stem cells are thought to be responsible for treatment resistance in glioblastoma, an aggressive brain cancer with poor patient outcomes. However, the regulation of quiescence in glioblastoma cells involves a myriad of intrinsic and extrinsic mechanisms that are not fully understood. In this review, we synthesise the literature on quiescence regulatory mechanisms in the context of glioblastoma and propose an ecological perspective to stemness-like phenotypes anchored to the contemporary concepts of niche theory. From this perspective, the cell cycle regulation is multiscale and multidimensional, where the niche dimensions extend to extrinsic variables in the tumour microenvironment that shape cell fate. Within this conceptual framework and powered by ecological niche modelling, the discovery of microenvironmental variables related to hypoxia and mechanosignalling that modulate proliferative plasticity and intratumor immune activity may open new avenues for therapeutic targeting of emerging biological vulnerabilities in glioblastoma.
Hydrophobicity-Driven Increases in Editing in Mitochondrial mRNAs during the Evolution of Kinetoplastids
Authors: Fanny Rusman, Noelia Floridia-Yapur, Anahí G Díaz, Tatiana Ponce, Patricio Diosque, Nicolás Tomasini
Journal: Molecular Biology and Evolution (2023)

Abstract Kinetoplastids are a diverse group of flagellates which exhibit editing by insertion/deletion of Us in the mitochondrial mRNAs. Some mRNAs require editing to build most of their coding sequences, a process known as pan-editing. Evidence suggests that pan-editing is an ancestral feature in kinetoplastids. Here, we investigate how the transition from nonedited to pan-edited states occurred. The mitochondrial mRNAs and protein sequences from nine kinetoplastids and related groups (diplonemids, euglenids, and jakobids) were analyzed. RNA editing increased protein hydrophobicity to extreme values by introducing Us in the second codon position, despite the absence of editing preferences related to codon position. In addition, hydrophobicity was maintained by purifying selection in species that lost editing by retroposition of the fully edited mRNA. Only a few hydrophobic to hydrophilic amino acid changes were inferred for such species. In the protein secondary structure, these changes occurred spatially close to other hydrophilic residues. The analysis of coevolving sites showed that multiple changes are required together for hydrophobicity to be lost, which suggest the proteins are locked into extended hydrophobicity. Finally, an analysis of the NAD7 protein–protein interactions showed they can also influence hydrophobicity increase in the protein and where editing can occur in the mRNA. In conclusion, our results suggest that protein hydrophobicity has influenced editing site selection and how editing expanded in mRNAs. In effect, the hydrophobicity increase was entrenched by a neutral ratchet moved by a mutational pressure to introduce Us, thus helping to explain both RNA editing increase and, possibly, persistence.
Population Genomic Evidence of Adaptive Response during the Invasion History of<i>Plasmodium falciparum</i>in the Americas
Authors: Margaux J M Lefebvre, Josquin Daron, Eric Legrand, Michael C Fontaine, Virginie Rougeron, Franck Prugnolle
Journal: Molecular Biology and Evolution (2023)

Plasmodium falciparum, the most virulent agent of human malaria, spread from Africa to all continents following the out-of-Africa human migrations. During the transatlantic slave trade between the 16th and 19th centuries, it was introduced twice independently to the Americas where it adapted to new environmental conditions (new human populations and mosquito species). Here, we analyzed the genome-wide polymorphisms of 2,635 isolates across the current P. falciparum distribution range in Africa, Asia, Oceania, and the Americas to investigate its genetic structure, invasion history, and selective pressures associated with its adaptation to the American environment. We confirmed that American populations originated from Africa with at least two independent introductions that led to two genetically distinct clusters, one in the North (Haiti and Colombia) and one in the South (French Guiana and Brazil), and an admixed Peruvian group. Genome scans revealed recent and more ancient signals of positive selection in the American populations. Particularly, we detected positive selection signals in genes involved in interactions with hosts (human and mosquito) cells and in genes involved in resistance to malaria drugs in both clusters. Analyses suggested that for five genes, adaptive introgression between clusters or selection on standing variation was at the origin of this repeated evolution. This study provides new genetic evidence on P. falciparum colonization history and on its local adaptation in the Americas.
Engineered Curli Nanofilaments as a Self‐Adjuvanted Antigen Delivery Platform
Authors: Félix Lamontagne, Dominic Arpin, Mélanie Côté‐Cyr, Vinay Khatri, Philippe St‐Louis, Laurie Gauthier, Denis Archambault, Steve Bourgault
Journal: Advanced Healthcare Materials (2023)

Abstract Proteinaceous nanoparticles constitute efficient antigen delivery systems in vaccine formulations due to their size and repetitive nature that mimic most invading pathogens and promote immune activation. Nonetheless, the coadministration of an adjuvant with subunit nanovaccines is usually required to induce a robust, long‐lasting, and protective immune response. Herein, the protein Curli‐specific gene A (CsgA), which is known to self‐assemble into nanofilaments contributing to bacterial biofilm, is exploited to engineer an intrinsically immunostimulatory antigen delivery platform. Three repeats of the M2e antigenic sequence from the influenza A virus matrix 2 protein are merged to the N‐terminal domain of engineered CsgA proteins. These chimeric 3M2e‐CsgA spontaneously self‐assemble into antigen‐displaying cross‐ β ‐sheet nanofilaments that activate the heterodimeric toll‐like receptors 2 and 1. The resulting nanofilaments are avidly internalized by antigen‐presenting cells and stimulate the maturation of dendritic cells. Without the need of any additional adjuvants, both assemblies show robust humoral and cellular immune responses, which translate into complete protection against a lethal experimental infection with the H1N1 influenza virus. Notably, these CsgA‐based nanovaccines induce neither overt systemic inflammation, nor reactogenicity, upon mice inoculation. These results highlight the potential of engineered CsgA nanostructures as self‐adjuvanted, safe, and versatile antigen delivery systems to fight infectious diseases.
The Apple Watch spO2 sensor and outliers in healthy users
Authors: Christina Schröder, Robert Förster, Daniel R. Zwahlen, Paul Windisch
Journal: npj Digital Medicine (2023)

It is unclear how frequently the Apple Watch produces spO2 measurements outside of the normal range in healthy individuals at rest. We conducted a head-to-head comparison in 38 healthy individuals between two watches and two medical-grade pulse oximeters. Fourteen percent of watch measurements yielded spO2 values below 95%, with no values below 92%. Results suggest that outliers measured by the watch should not be a cause for concern in otherwise healthy individuals.
Blood Test Increases Colorectal Cancer Screening in Persons Who Declined Colonoscopy and Fecal Immunochemical Test: A Randomized Controlled Trial
Authors: Peter S. Liang, Anika Zaman, Anne Kaminsky, Yongyan Cui, Gabriel Castillo, Craig T. Tenner, Scott E. Sherman, Jason A. Dominitz
Journal: Clinical Gastroenterology and Hepatology (2023)
Retroperitoneal Teratoma With Malignant Transformation
Authors: Kit Fai Lee, Eugene Yee Juen Lo, Sunny Yue Sun Cheung
Journal: Clinical Gastroenterology and Hepatology (2023)

A 48-year-old man presented with worsening epigastric pain that had started a few years prior. Computed tomography (CT) of the abdomen showed a left upper quadrant 27 × 19 × 15 cm retroperitoneal encapsulated complex lesion containing fatty and cystic components (Figures A and B). Laparotomy with complete excision of the lesion was performed, with uneventful postoperative course. Gross examination showed a unilocular cyst with collection of cheese-like yellowish material admixed with hair (Figure C). Foci of calcification were noted. Microscopic examination showed that the cyst wall was composed of fibrous tissue, skin and skin appendages, skeletal muscle, smooth muscle, and lymph node and ganglioneuroma tissue, which were consistent with a mature teratoma. However, a focal 2.5 cm squamous cell carcinoma was noted arising from the teratoma. Hematoxylin-eosin stain showed keratinizing squamous cell carcinoma arranging in infiltrative sheets and nests (Figure D). The patient remained well, and serial follow-up CTs did not reveal any recurrent disease up to 8 years after surgery. Teratoma is an uncommon congenital tumor that arises from pluripotential embryonic cells. It contains derivatives of 2 or more germ cell layers (ectoderm, endoderm, and mesoderm) and therefore can contain different somatic tissues such as hair, teeth, bone, and even entire body organs. Up to 25% of adult retroperitoneal teratomas can undergo malignant transformation, and the most common type is squamous cell carcinoma.
THE FUTURE OF THE MEDICAL PROFESSION
Journal: JAMA (2010)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
ROS Scavenging Nanozyme Modulates Immunosuppression for Sensitized Cancer Immunotherapy
Authors: Wenjing Mo, Shujie Liu, Xiaozhi Zhao, Fayun Wei, Yuhang Li, Xinan Sheng, Wenmin Cao, Meng Ding, Wenlong Zhang, Xiaoqing Chen, Longxiyu Meng, Sheng Yao, Wenli Diao, Hui Wei, Hongqian Guo
Journal: Advanced Healthcare Materials (2023)

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), two immunosuppressive myeloid components within the tumor microenvironment (TME), represent fundamental barriers in cancer immunotherapy, whereas current nanomedicines rarely exert dual modulatory roles on these cell types simultaneously. Reactive oxygen species (ROS) not only mediates MDSC-induced immunosuppression but also triggers differentiation and polarization of M2-TAMs. Herein, an ROS scavenging nanozyme, Zr-CeO, with enhanced superoxide dismutase- and catalase-like activities for renal tumor growth inhibition is reported. Mechanistically, intracellular ROS scavenging by Zr-CeO significantly attenuates MDSC immunosuppression via dampening the unfolded protein response, hinders M2-TAM polarization through the ERK and STAT3 pathways, but barely affects neoplastic cells and cancer-associated fibroblasts. Furthermore, Zr-CeO enhances the antitumor effect of PD-1 inhibition in murine renal and breast tumor models, accompanied with substantially decreased MDSC recruitment and reprogrammed phenotype of TAMs in the tumor mass. Upon cell isolation, reversed immunosuppressive phenotypes of MDSCs and TAMs are identified. In addition, Zr-CeO alone or combination therapy enhances T lymphocyte infiltration and IFN-γ production within the TME. Collectively, a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers is provided.
Enhancing anti-tumor immunity through liposomal oxaliplatin and localized immunotherapy via STING activation
Authors: Zili Gu, Yang Hao, Timo Schomann, Ferry Ossendorp, Peter ten Dijke, Luis J. Cruz
Journal: Journal of Controlled Release (2023)

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising approach for anti-cancer immunotherapy by bridging innate and adaptive immunity. Recent evidence suggests that chemotherapy-induced DNA damage can directly induce dendritic cell (DC) maturation and recruitment, which synergizes with STING activation to enhance anti-tumor effects. As an immunogenic cell death (ICD) inducer, oxaliplatin generates massive double-stranded DNA (dsDNA) crosslinks, release of tumor-associated antigens and promoting the "eat me" signal. STING activation improves antigen immunogenicity, which can promote T cell activation and infiltration. In this study, we developed liposomes encapsulating oxaliplatin and combine this formulation with a STING agonist (ADU-S100) for treating colorectal cancer. The liposomes efficiently inhibited the proliferation of tumor cells while induced ICD in CT26 colorectal cancer cells, which enhanced dendritic cell maturation and phagocytosis in vitro. The liposome-based immunochemotherapy exhibited the strongest efficacy, resulting in complete remission upon tumor inoculation. Mechanistic studies showed this potent anti-cancer effect was related to the significant recruitment of infiltrating CD8 and CD4 T cells, reduction of suppressive Treg cells, and a shift in the phenotype of tumor-associated suppressive macrophages that promote cancer to immune stimulating macrophages. Thus, our study demonstrated the potential of combining oxaliplatin-loaded liposomes with a STING agonist to reduce tumor growth by regulating the immunosuppressive state in the tumor.
Cardiovascular Disease Risk Factors in Women: The Impact of Race and Ethnicity: A Scientific Statement From the American Heart Association
Authors: Laxmi S. Mehta, Gladys P. Velarde, Jennifer Lewey, Garima Sharma, Rachel M. Bond, Ana Navas-Acien, Amanda M. Fretts, Gayenell S. Magwood, Eugene Yang, Roger S. Blumenthal, Rachel-Maria Brown, Jennifer H. Mieres
Journal: Circulation (2023)

Cardiovascular disease is the leading cause of death in women, yet differences exist among certain racial and ethnic groups. Aside from traditional risk factors, behavioral and environmental factors and social determinants of health affect cardiovascular health and risk in women. Language barriers, discrimination, acculturation, and health care access disproportionately affect women of underrepresented races and ethnicities. These factors result in a higher prevalence of cardiovascular disease and significant challenges in the diagnosis and treatment of cardiovascular conditions. Culturally sensitive, peer-led community and health care professional education is a necessary step in the prevention of cardiovascular disease. Equitable access to evidence-based cardiovascular preventive health care should be available for all women regardless of race and ethnicity; however, these guidelines are not equally incorporated into clinical practice. This scientific statement reviews the current evidence on racial and ethnic differences in cardiovascular risk factors and current cardiovascular preventive therapies for women in the United States.
Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders
Authors: Alessandro Bonifazi, Fabio Del Bello, Gianfabio Giorgioni, Alessandro Piergentili, Elizabeth Saab, Luca Botticelli, Carlo Cifani, Emanuela Micioni Di Bonaventura, Maria Vittoria Micioni Di Bonaventura, Wilma Quaglia
Journal: Medicinal Research Reviews (2023)

Abstract Orexin‐A and orexin‐B, also named hypocretin‐1 and hypocretin‐2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein‐coupled receptors, namely orexin receptor type 1 (OX1‐R) and type 2 (OX2‐R), which share 64% amino acid identity. Given the wide expression of OX‐Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep‐wake cycle regulation (mainly mediated by OX2‐R), emotion, panic‐like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1‐R), both subtypes represent targets of interest for many structure–activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual‐orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1‐R and OX2‐R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype‐selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1‐R/OX2‐R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX‐R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly‐pharmacology applications and multitarget ligands have also been considered.
Fast and furious: The neutrophil and its armamentarium in health and disease
Authors: Mieke Metzemaekers, Bert Malengier‐Devlies, Mieke Gouwy, Lien De Somer, Fernando de Queiroz Cunha, Ghislain Opdenakker, Paul Proost
Journal: Medicinal Research Reviews (2023)

Abstract Neutrophils are powerful effector cells leading the first wave of acute host‐protective responses. These innate leukocytes are endowed with oxidative and nonoxidative defence mechanisms, and play well‐established roles in fighting invading pathogens. With microbicidal weaponry largely devoid of specificity and an all‐too‐well recognized toxicity potential, collateral damage may occur in neutrophil‐rich diseases. However, emerging evidence suggests that neutrophils are more versatile, heterogeneous, and sophisticated cells than initially thought. At the crossroads of innate and adaptive immunity, neutrophils demonstrate their multifaceted functions in infectious and noninfectious pathologies including cancer, autoinflammation, and autoimmune diseases. Here, we discuss the kinetics of neutrophils and their products of activation from bench to bedside during health and disease, and provide an overview of the versatile functions of neutrophils as key modulators of immune responses and physiological processes. We focus specifically on those activities and concepts that have been validated with primary human cells.
Missing melanomas in England during the COVID-19 pandemic: 2485 fewer melanoma diagnoses in 2020 than in 2019
Authors: Lena S Ibrahim, Zoe C Venables, Sean McPhail, Nick J Levell
Journal: British Journal of Dermatology (2023)

Malignant melanoma (MM) can have a high mortality if diagnosed late. Three waves of COVID-19 in 2020–21 led to periods of reduced healthcare provision in England. Although most cancer services were maintained, factors such as patient anxiety, staff and facility redeployment, and staff sickness delayed cancer diagnoses. We aimed to investigate the effect of the COVID-19 pandemic on MM diagnoses and stage at presentation in England
Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate‐to‐severe atopic dermatitis
Authors: Jan Hartmann, Lucas Moitinho‐Silva, Nicole Sander, Inken Harder, Robert Häsler, Elke Rodriguez, Eva Haufe, Andreas Kleinheinz, Susanne Abraham, Annice Heratizadeh, Elke Weisshaar, Knut Schäkel, Christiane Handrick, Matthias Augustin, Andreas Wollenberg, Petra Staubach‐Renz, Konstantin Ertner, Michael Sticherling, Beate Schwarz, Sven Quist, Franca Wiemers, Florian Schenck, Julia Wildberger, Lukas Tittmann, Wolfgang Lieb, Jochen Schmitt, Thomas Werfel, Stephan Weidinger
Journal: Allergy (2023)

Abstract Background Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry. Methods Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population‐based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI). Results We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non‐lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine. Conclusions Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL‐4RA blockade on the microbiome.